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Werner Siegmund - One of the best experts on this subject based on the ideXlab platform.
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modeling the heterogeneous intestinal absorption of Propiverine extended release
European Journal of Pharmaceutical Sciences, 2015Co-Authors: Pakawadee Sermsappasuk, Michael Weiss, Werner SiegmundAbstract:Abstract Propiverine is a widely used antimuscarinic drug with bioavailability that is limited by intestinal first-pass extraction. To study the apparent heterogeneity in intestinal first-pass extraction, we performed a population analysis of oral concentration–time data measured after administration of an extended-release formulation of Propiverine in ten healthy subjects. Using an inverse Gaussian function as input model, the assumption that the systemically available fraction increases as a sigmoidal function of time considerably improved the fit. The step-like increase in this fraction at time t = 3.7 h predicted by the model suggests that Propiverine is predominantly absorbed in colon. A nearly perfect correlation was found between the estimates of bioavailability and mean dissolution time.
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influence of a fat rich meal on bioavailability of extended release and immediate release Propiverine
The Journal of Clinical Pharmacology, 2012Co-Authors: Werner Siegmund, Frieder Schnabel, Cornelia Feustel, Joachim Siegert, K Richter, Wilhelm KirchAbstract:The muscarinic receptor antagonist Propiverine is unique insofar as extended-release (ER) tablets are of higher bioavailability than immediate-release (IR) tablets; this is caused by lower "first-pass" elimination of Propiverine via CYP3A4 and efflux transporters in the distal small intestine and colon. Food may influence gastrointestinal transiting and, in turn, may affect regional absorption of Propiverine IR and ER. Therefore, food effects on disposition of 30 mg IR and 45 mg ER were measured in a randomized, open, 4-period interaction study in 24 healthy participants. In fasting participants, ER had higher bioavailability than IR (F(rel) = 169%, P = .03). Fat-rich meal did not change the disposition of ER markedly (AUC(0-∞) ratio, 1.00 [90% confidence interval (CI), 0.90-1.11], C(max) ratio, 0.97 [0.87-1.09]). However, C(max) and renal A(e) of the major N-oxidized metabolite (M-5) significantly increased, whereas t(1/2) decreased. By eating a fat-rich meal before administration, the differences in absorption of IR and ER were nearly abolished (AUC(0-∞) ratio for Propiverine, 1.12 [90% CI, 0.95-1.33]; AUC(0-∞) ratio for M-5, 0.89 [0.82-0.95]). In conclusion, Propiverine ER has higher bioavailability than IR and no positive food effect because it reaches, independently of food, intestinal absorption areas with lower metabolism and efflux transport, which results in constant absorption rates.
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oral absorption of Propiverine solution and of the immediate and extended release dosage forms influence of regioselective intestinal elimination
European Journal of Clinical Pharmacology, 2008Co-Authors: K May, Thomas Giessmann, Danilo Wegner, Reinhard Oertel, Christiane Modess, Stefan Oswald, Manfred Braeter, Werner SiegmundAbstract:The muscarine receptor antagonist Propiverine in immediate release tablet form (IR) undergoes presystemic elimination mediated by CYP450 enzymes and intestinal efflux transporters. The aim of our study with Propiverine IR and extended release (ER) was to determine whether Propiverine disposition is dose linear, to compare the pharmacokinetics of Propiverine in oral solution with IR and ER and to show how absorption rate is associated with bioavailability. The pharmacokinetics of Propiverine administered as intravenous Propiverine (15 mg), 10, 15, and 30 mg Propiverine IR, an oral Propiverine solution (15 mg) and 10, 15, 30, and 45 mg Propiverine ER were measured in two randomized, controlled, single-dose, five-period, cross-over studies, with each case involving a study cohort of ten healthy Caucasian subjects. Disposition of Propiverine IR and ER was not dose-related. The bioavailability of ER was 64.5 ± 16.1% compared to 50.3 ± 13.4% (non-significant) after administration of the IR and Propiverine solution (42.6 ± 14.8%, p < 0.05). The mean absorption time (MAT) of ER (14.2 ± 4.79 h) was significantly longer than that of the solution and IR (3.94 ± 4.14 and 0.38 ± 3.79 h, respectively; both p < 0.05). The bioavailability of Propiverine was significantly correlated to the MAT (r = 0.521, p < 0.001). Renal excretion of the metabolite M-23 after Propiverine ER administration (6.7 ± 2.7%) was significantly lower than that after administration of the oral solution (10 ± 2.2%) and of IR (9.8 ± 2.7%; both p < 0.05). The bioavailability of Propiverine appears to be dependent on the intestinal site of dissolution and, consequently, on the extent of presystemic intestinal elimination.
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determination of Propiverine and its metabolites in rat samples by liquid chromatography tandem mass spectrometry
Journal of Chromatography A, 2007Co-Authors: Reinhard Oertel, Werner Siegmund, B Kilian, Wilhelm KirchAbstract:A liquid chromatography-tandem mass spectrometric (LC-MS-MS) method was developed and validated for the determination of the anticholinergic and antimuscarinc drug Propiverine and eight of its metabolites in serum, urine, faeces and different tissue samples of rats. Samples containing Propiverine and its metabolites in serum and urine and in the supernatants of faeces and tissue homogenates were extracted and cleaned up using an automated solid phase extraction (SPE) method. An external calibration was used. The analytes were measured employing the multiple reaction monitoring mode (MRM). A sufficient response over the range of 10-1000 ng/ml was demonstrated. The lower limit of quantification of the nine substances was 10 ng/ml. The presented method is suitable for pharmacokinetic or toxicokinetic studies. To look for additional unknown metabolites, the LC-MS-MS system operated in the precursor ion mode using typical product ions of Propiverine and of its metabolites. With the help of the chromatographic behaviour and typical fragment ions of the unknown metabolites, it was possible to elucidate their structure. Five until now unknown metabolites were found in the urine and faeces samples. However, without reference substances, a quantification of these analytes was not possible.
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influence of Propiverine on hepatic microsomal cytochrome p450 enzymes in male rats
Drug Metabolism and Disposition, 2003Co-Authors: R Walter, C Ullmann, D Thummler, Werner SiegmundAbstract:The bladder spasmolytics Propiverine was shown to induce hepatic cytochrome P450 (P450) and aminopyrine and aniline oxidation in rats. To characterize the type of enzyme induction and its dose dependence, activities of seven hepatic microsomal P450-dependent monooxygenases were measured in 72 male LEW1A albino rats (body weight 236-295 g) after oral treatment with 0.5, 2, 6, and 60 mg/kg of Propiverine hydrochloride for 5 days and compared with the effects of 40 mg/kg beta-naphthoflavone, 10 mg/kg phenobarbital, and 20 mg/kg dexamethasone (each group, n = 8). CYP2B expression was measured by Western blotting. Furthermore, the inhibitory potency of Propiverine on P450 enzymes was evaluated in competition assays with three most specific monooxygenases. Results show that Propiverine induced several monooxygenases and CYP2B expression dose dependently. The effects were well comparable with a phenobarbital-type inducer with 60 mg/kg being equipotent to 10 mg/kg phenobarbital. Furthermore, Propiverine in low concentrations inhibited pentylresorufin O-dealkylase (for CYP2B) in vitro. In conclusion, Propiverine is a phenobarbital-type inducer on hepatic P450 enzymes in rats in doses about 100-times above the therapeutic doses in man.
Wilhelm Kirch - One of the best experts on this subject based on the ideXlab platform.
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influence of a fat rich meal on bioavailability of extended release and immediate release Propiverine
The Journal of Clinical Pharmacology, 2012Co-Authors: Werner Siegmund, Frieder Schnabel, Cornelia Feustel, Joachim Siegert, K Richter, Wilhelm KirchAbstract:The muscarinic receptor antagonist Propiverine is unique insofar as extended-release (ER) tablets are of higher bioavailability than immediate-release (IR) tablets; this is caused by lower "first-pass" elimination of Propiverine via CYP3A4 and efflux transporters in the distal small intestine and colon. Food may influence gastrointestinal transiting and, in turn, may affect regional absorption of Propiverine IR and ER. Therefore, food effects on disposition of 30 mg IR and 45 mg ER were measured in a randomized, open, 4-period interaction study in 24 healthy participants. In fasting participants, ER had higher bioavailability than IR (F(rel) = 169%, P = .03). Fat-rich meal did not change the disposition of ER markedly (AUC(0-∞) ratio, 1.00 [90% confidence interval (CI), 0.90-1.11], C(max) ratio, 0.97 [0.87-1.09]). However, C(max) and renal A(e) of the major N-oxidized metabolite (M-5) significantly increased, whereas t(1/2) decreased. By eating a fat-rich meal before administration, the differences in absorption of IR and ER were nearly abolished (AUC(0-∞) ratio for Propiverine, 1.12 [90% CI, 0.95-1.33]; AUC(0-∞) ratio for M-5, 0.89 [0.82-0.95]). In conclusion, Propiverine ER has higher bioavailability than IR and no positive food effect because it reaches, independently of food, intestinal absorption areas with lower metabolism and efflux transport, which results in constant absorption rates.
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determination of Propiverine and its metabolites in rat samples by liquid chromatography tandem mass spectrometry
Journal of Chromatography A, 2007Co-Authors: Reinhard Oertel, Werner Siegmund, B Kilian, Wilhelm KirchAbstract:A liquid chromatography-tandem mass spectrometric (LC-MS-MS) method was developed and validated for the determination of the anticholinergic and antimuscarinc drug Propiverine and eight of its metabolites in serum, urine, faeces and different tissue samples of rats. Samples containing Propiverine and its metabolites in serum and urine and in the supernatants of faeces and tissue homogenates were extracted and cleaned up using an automated solid phase extraction (SPE) method. An external calibration was used. The analytes were measured employing the multiple reaction monitoring mode (MRM). A sufficient response over the range of 10-1000 ng/ml was demonstrated. The lower limit of quantification of the nine substances was 10 ng/ml. The presented method is suitable for pharmacokinetic or toxicokinetic studies. To look for additional unknown metabolites, the LC-MS-MS system operated in the precursor ion mode using typical product ions of Propiverine and of its metabolites. With the help of the chromatographic behaviour and typical fragment ions of the unknown metabolites, it was possible to elucidate their structure. Five until now unknown metabolites were found in the urine and faeces samples. However, without reference substances, a quantification of these analytes was not possible.
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pharmacokinetics and safety of Propiverine in patients with fatty liver disease
European Journal of Clinical Pharmacology, 1998Co-Authors: M Siepmann, D Thummler, A Nokhodian, Wilhelm KirchAbstract:Objective: The present study was designed to assess the pharmacokinetics of Propiverine after single and multiple dosing in patients with and without fatty liver disease.
Ursula Ravens - One of the best experts on this subject based on the ideXlab platform.
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the muscarinic receptor antagonist Propiverine exhibits α1 adrenoceptor antagonism in human prostate and porcine trigonum
World Journal of Urology, 2011Co-Authors: Melinda Wuest, Manfred Braeter, Manfred P Wirth, Gerhard Strugala, Lambertus P W Witte, Martina B Michelreher, Stefan Propping, Martin C Michel, Ursula RavensAbstract:Purpose Combination therapy of male lower urinary tract symptoms with α1-adrenoceptor and muscarinic receptor antagonists attracts increasing interest. Propiverine is a muscarinic receptor antagonist possessing additional properties, i.e., block of L-type Ca2+ channels. Here, we have investigated whether Propiverine and its metabolites can additionally antagonize α1-adrenoceptors.
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effects of three metabolites of Propiverine on voltage dependent l type calcium currents in human atrial myocytes
European Journal of Pharmacology, 2008Co-Authors: Melinda Wuest, Manfred Braeter, Torsten Christ, Nicole Hiller, Ursula RavensAbstract:The non-selective muscarinic receptor antagonist Propiverine impairs L-type Ca(2+) currents (I(Ca,L)) in human detrusor smooth muscle cells and atrial cardiomyocytes. Here, we have investigated the effects of three metabolites of Propiverine on human cardiac I(Ca,L). Propiverine reduced I(Ca)(,L) with a -logIC(50) [M] value of 4.1, M-5 only showed minor effect on I(Ca)(,L) at high concentrations, M-6 did not influence I(Ca)(,L) at all. Like the parent compound M-14 also reduced I(Ca)(,L) (-logIC(50) [M]=4.6). We conclude, that Propiverine and M-14 reduce cardiac I(Ca)(,L) at higher concentrations than in detrusor cells and therefore preferentially reduce I(Ca)(,L) in the urinary bladder than in the heart.
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electrophysiological profile of Propiverine relationship to cardiac risk
Naunyn-schmiedebergs Archives of Pharmacology, 2008Co-Authors: Torsten Christ, Manfred Braeter, Melinda Wuest, Erich Wettwer, Frank Donath, P Champeroux, Serge Richard, Ursula RavensAbstract:Drugs that prolong the QT interval by blocking human ether-a-go-go (HERG) channels may enhance the risk of ventricular arrhythmia. The spasmolytic drug Propiverine is widely used for the therapy of overactive bladder (OAB). Here, we have investigated the effects of Propiverine on cardiac ion channels and action potentials as well as on contractile properties of cardiac tissue, in order to estimate its cardiac safety profile, because other drugs used in this indication had to be withdrawn due to safety reasons. Whole-cell patch clamp technique was used to record the following cardiac ion currents: rapidly and slowly activating delayed rectifier K+ current (IKr, IKs), ultra rapidly activating delayed rectifier K+ current (IKur), inwardly rectifying K+ current IK1, transient outward K+ current (Ito), and L-type Ca2+ current (ICa,L). Action potentials in cardiac tissue biopsies were recorded with conventional microelectrodes. The torsade de pointes screening assay (TDPScreenTM) was used for drug scoring. Propiverine blocked in a concentration-dependent manner HERG channels expressed in HEK293 cells, as well as native IKr current in ventricular myocytes of guinea pig (IC50 values: 10 μM and 1.8 μM respectively). At high concentrations (100 μM), Propiverine suppressed IKs. IK1 and the transient outward current Ito and IKur were not affected. In guinea-pig ventricular and human atrial myocytes, Propiverine also blocked ICa,L (IC50 values: 34.7 μM and 41.7 μM, respectively) and reduced force of contraction. Despite block of IKr, action potential duration was not prolonged in guinea-pig and human ventricular tissue, but decreased progressively until excitation failed altogether. Similar effects were observed in dog Purkinje fibers. Propiverine obtained a low score in the TDPScreenTM. In conclusion, in vitro and in vivo studies of Propiverine do not provide evidence for an enhanced cardiovascular safety risk. We propose that lack of torsadogenic risk of Propiverine is related to enhancement of repolarization reserve by block of ICa,L.
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Propiverine and metabolites: differences in binding to muscarinic receptors and in functional models of detrusor contraction
Naunyn-Schmiedeberg's Archives of Pharmacology, 2006Co-Authors: Melinda Wuest, Manfred Braeter, Anke Weiss, Magali Waelbroeck, Lutz-ullrich Kelly, Oliver W. Hakenberg, Ursula RavensAbstract:Propiverine is a commonly used antimuscarinic drug used as therapy for symptoms of an overactive bladder. Propiverine is extensively biotransformed into several metabolites that could contribute to its spasmolytic action. In fact, three Propiverine metabolites (M-5, M-6 and M-14) have been shown to affect various detrusor functions, including contractile responses and L-type calcium-currents, in humans, pigs and mice, albeit with different potency. The aim of our study was to provide experimental evidence for the relationship between the binding of Propiverine and its metabolites to human muscarinic receptor subtypes (hM_1–hM_5) expressed in chinese hamster ovary cells, and to examine the effects of these compounds on muscarinic receptor-mediated detrusor function. Propiverine, M-5, M-6 and M-14 bound to hM_1–hM_5 receptors with the same order of affinity for all five subtypes: M-6 > Propiverine > M-14 > M-5. In HEK-293 cells expressing hM_3, carbachol-induced release of intracellular Ca^2+ ([Ca^2+]_i) was suppressed by Propiverine and its metabolites; the respective concentration-response curves for carbachol-induced Ca^2+-responses were shifted to the right. At higher concentrations, Propiverine and M-14, but not M-5 and M-6, directly elevated [Ca^2+]_i. These results were confirmed for Propiverine in human detrusor smooth muscle cells (hDSMC). Propiverine and the three metabolites decreased detrusor contractions evoked by electric field stimulation in a concentration-dependent manner, the order of potency being the same as the order of binding affinity. We conclude that, in comparison with the parent compound, loss of the aliphatic side chain in Propiverine metabolites is associated with higher binding affinity to hM_1–hM_5 receptors and higher functional potency. Change from a tertiary to a secondary amine (M-14) results in lower binding affinity and reduced potency. Oxidation of the nitrogen (M-5) further lowers binding affinity as well as functional potency.
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juvenile pig detrusor effects of Propiverine and three of its metabolites
European Journal of Pharmacology, 2005Co-Authors: Melinda Wuest, Manfred Braeter, Christian Schoeberl, Ursula RavensAbstract:In isolated detrusor strips, Propiverine is known to be effective to decrease contractions elicited by electric field stimulation (EFS). Here we investigated whether the metabolites M-5, M-6 and M-14 of Propiverine retain the pharmacological properties of the parent compound also in juvenile organisms. EFS-induced contractions of detrusor strips from juvenile pigs are more sensitive to atropine than strips from mature pigs. The atropine-resistant component of contraction is also significantly larger in juvenile pigs. Propiverine, its metabolites M-5, M-14 and also tolterodine completely reduced detrusor contraction in juvenile pigs. M-6 almost did not affect atropine-resistant contractions. We conclude that juvenile pig detrusors possess a higher atropine-resistant component of EFS-elicited contraction. Nevertheless order of potency and efficacy of Propiverine and its metabolites M-5 and M-14 are similar in juvenile and mature pigs, while M-6 only reduces atropine-sensitive contractions in the juvenile organism.
Manfred Braeter - One of the best experts on this subject based on the ideXlab platform.
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the muscarinic receptor antagonist Propiverine exhibits α1 adrenoceptor antagonism in human prostate and porcine trigonum
World Journal of Urology, 2011Co-Authors: Melinda Wuest, Manfred Braeter, Manfred P Wirth, Gerhard Strugala, Lambertus P W Witte, Martina B Michelreher, Stefan Propping, Martin C Michel, Ursula RavensAbstract:Purpose Combination therapy of male lower urinary tract symptoms with α1-adrenoceptor and muscarinic receptor antagonists attracts increasing interest. Propiverine is a muscarinic receptor antagonist possessing additional properties, i.e., block of L-type Ca2+ channels. Here, we have investigated whether Propiverine and its metabolites can additionally antagonize α1-adrenoceptors.
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effects of three metabolites of Propiverine on voltage dependent l type calcium currents in human atrial myocytes
European Journal of Pharmacology, 2008Co-Authors: Melinda Wuest, Manfred Braeter, Torsten Christ, Nicole Hiller, Ursula RavensAbstract:The non-selective muscarinic receptor antagonist Propiverine impairs L-type Ca(2+) currents (I(Ca,L)) in human detrusor smooth muscle cells and atrial cardiomyocytes. Here, we have investigated the effects of three metabolites of Propiverine on human cardiac I(Ca,L). Propiverine reduced I(Ca)(,L) with a -logIC(50) [M] value of 4.1, M-5 only showed minor effect on I(Ca)(,L) at high concentrations, M-6 did not influence I(Ca)(,L) at all. Like the parent compound M-14 also reduced I(Ca)(,L) (-logIC(50) [M]=4.6). We conclude, that Propiverine and M-14 reduce cardiac I(Ca)(,L) at higher concentrations than in detrusor cells and therefore preferentially reduce I(Ca)(,L) in the urinary bladder than in the heart.
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oral absorption of Propiverine solution and of the immediate and extended release dosage forms influence of regioselective intestinal elimination
European Journal of Clinical Pharmacology, 2008Co-Authors: K May, Thomas Giessmann, Danilo Wegner, Reinhard Oertel, Christiane Modess, Stefan Oswald, Manfred Braeter, Werner SiegmundAbstract:The muscarine receptor antagonist Propiverine in immediate release tablet form (IR) undergoes presystemic elimination mediated by CYP450 enzymes and intestinal efflux transporters. The aim of our study with Propiverine IR and extended release (ER) was to determine whether Propiverine disposition is dose linear, to compare the pharmacokinetics of Propiverine in oral solution with IR and ER and to show how absorption rate is associated with bioavailability. The pharmacokinetics of Propiverine administered as intravenous Propiverine (15 mg), 10, 15, and 30 mg Propiverine IR, an oral Propiverine solution (15 mg) and 10, 15, 30, and 45 mg Propiverine ER were measured in two randomized, controlled, single-dose, five-period, cross-over studies, with each case involving a study cohort of ten healthy Caucasian subjects. Disposition of Propiverine IR and ER was not dose-related. The bioavailability of ER was 64.5 ± 16.1% compared to 50.3 ± 13.4% (non-significant) after administration of the IR and Propiverine solution (42.6 ± 14.8%, p < 0.05). The mean absorption time (MAT) of ER (14.2 ± 4.79 h) was significantly longer than that of the solution and IR (3.94 ± 4.14 and 0.38 ± 3.79 h, respectively; both p < 0.05). The bioavailability of Propiverine was significantly correlated to the MAT (r = 0.521, p < 0.001). Renal excretion of the metabolite M-23 after Propiverine ER administration (6.7 ± 2.7%) was significantly lower than that after administration of the oral solution (10 ± 2.2%) and of IR (9.8 ± 2.7%; both p < 0.05). The bioavailability of Propiverine appears to be dependent on the intestinal site of dissolution and, consequently, on the extent of presystemic intestinal elimination.
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disposition and antimuscarinic effects of the urinary bladder spasmolytics Propiverine influence of dosage forms and circadian time rhythms
The Journal of Clinical Pharmacology, 2008Co-Authors: K May, Thomas Giessmann, Danilo Wegner, Reinhard Oertel, Kristin Westphal, Ulrike Adam, Markus M Lerch, Rolf Warzok, Werner Weitschies, Manfred BraeterAbstract:Propiverine extended release is expected to be better tolerated compared to immediate release tablets because of slower drug release and reduced formation of active metabolites in the colon. CYP3A4 and ABCC2, the major variables in pharmacokinetics of Propiverine, are less expressed in the colon. Therefore, disposition and pharmacodynamics of Propiverine were measured in a double-blind, double-dummy, crossover study with administration of 15 mg immediate release 3 times daily for 7 days compared to 45 mg extended release once daily for 7 days in 24 healthy subjects. Twelve subjects also received 15 mg Propiverine intravenously. Serum and urine Propiverine levels were measured repeatedly following oral administration on day 7 for up to 72 hours and correlated to duodenal expression of CYP3A4, ABCB1, and ABCC2. Propiverine immediate release 3 times daily was not different to extended release once daily in areas under the serum concentration-time curve (0-24 hours) and peak-trough fluctuation. The areas under the serum concentration-time curve of Propiverine immediate release was circadian-time-dependent, with the lowest values during the night. Disposition of intravenous Propiverine and Propiverine immediate release administered in the night was influenced by intestinal expression of ABCC2. We concluded that oral absorption of Propiverine is site-dependent and influenced by dosage form and circadian-time-dependent elimination processes.
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electrophysiological profile of Propiverine relationship to cardiac risk
Naunyn-schmiedebergs Archives of Pharmacology, 2008Co-Authors: Torsten Christ, Manfred Braeter, Melinda Wuest, Erich Wettwer, Frank Donath, P Champeroux, Serge Richard, Ursula RavensAbstract:Drugs that prolong the QT interval by blocking human ether-a-go-go (HERG) channels may enhance the risk of ventricular arrhythmia. The spasmolytic drug Propiverine is widely used for the therapy of overactive bladder (OAB). Here, we have investigated the effects of Propiverine on cardiac ion channels and action potentials as well as on contractile properties of cardiac tissue, in order to estimate its cardiac safety profile, because other drugs used in this indication had to be withdrawn due to safety reasons. Whole-cell patch clamp technique was used to record the following cardiac ion currents: rapidly and slowly activating delayed rectifier K+ current (IKr, IKs), ultra rapidly activating delayed rectifier K+ current (IKur), inwardly rectifying K+ current IK1, transient outward K+ current (Ito), and L-type Ca2+ current (ICa,L). Action potentials in cardiac tissue biopsies were recorded with conventional microelectrodes. The torsade de pointes screening assay (TDPScreenTM) was used for drug scoring. Propiverine blocked in a concentration-dependent manner HERG channels expressed in HEK293 cells, as well as native IKr current in ventricular myocytes of guinea pig (IC50 values: 10 μM and 1.8 μM respectively). At high concentrations (100 μM), Propiverine suppressed IKs. IK1 and the transient outward current Ito and IKur were not affected. In guinea-pig ventricular and human atrial myocytes, Propiverine also blocked ICa,L (IC50 values: 34.7 μM and 41.7 μM, respectively) and reduced force of contraction. Despite block of IKr, action potential duration was not prolonged in guinea-pig and human ventricular tissue, but decreased progressively until excitation failed altogether. Similar effects were observed in dog Purkinje fibers. Propiverine obtained a low score in the TDPScreenTM. In conclusion, in vitro and in vivo studies of Propiverine do not provide evidence for an enhanced cardiovascular safety risk. We propose that lack of torsadogenic risk of Propiverine is related to enhancement of repolarization reserve by block of ICa,L.
Gerd Murtz - One of the best experts on this subject based on the ideXlab platform.
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efficacy and tolerability of Propiverine hydrochloride extended release compared with immediate release in patients with neurogenic detrusor overactivity
Spinal Cord, 2013Co-Authors: M Stohrer, Gerd Murtz, G Kramer, W Warnack, G Primus, V Jinga, A Manumarin, N Calomfirescu, G StrugalaAbstract:Efficacy and tolerability of Propiverine hydrochloride extended-release compared with immediate-release in patients with neurogenic detrusor overactivity
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urodynamic effects of Propiverine in children and adolescents with neurogenic bladder results of a prospective long term study
Journal of Pediatric Urology, 2012Co-Authors: Heinrich Schultebaukloh, Gerd Murtz, Gerhard Strugala, Theodor Michael, Kurt Miller, Gert Heine, Paul F Austin, Helmut H KnispelAbstract:Abstract Objective To evaluate prospectively the efficacy and tolerability of Propiverine for long-term treatment of neurogenic detrusor overactivity (NDO) in children. Materials and methods 17 children and adolescents with NDO (10 female, 7 male; average age at last consultation 13.0 years) were evaluated during long-term treatment with Propiverine (0.8 mg/kg body weight/day). Outcome measurements included urodynamic parameters, continence, hydronephrosis and tolerability of Propiverine. Results Average follow-up was 3.6 years (range 2.0–5.9). The average maximum detrusor pressure was 33.2 ± 4.8 cmH2O and bladder compliance was 20.0 ± 5.4 ml/cmH2O at the last follow-up visit. Maximum cystometric bladder capacity (MCBC) within the normal range was attained in 11 patients; it was still reduced (average of 61% of expected MCBC) in the remaining 6. Incontinence occurred on average once per day. Hydronephrosis was classified for each renal unit separately: grade 0 was measured in 26 and 22 cases, grade 1 or 2 in 6 and 8 cases, grade 3 or 4 in 2 and 4 cases pre and post treatment, respectively. In 6/17 patients adjuvant intravesical oxybutynin was applied, in 4 out of these 6 patients more invasive procedures, such as untethering, augmentation cystoplasty or botulinum toxin injections, were necessitated. Propiverine monotherapy was well tolerated in 11/17 patients. No serious adverse events were encountered during the study period. Conclusion Long-term efficacy and tolerability of Propiverine for NDO in children and adolescents is promising: clinically relevant improvements in key urodynamic outcomes were paralleled by improvements in incontinence score.
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efficacy tolerability and safety of Propiverine hydrochloride in comparison to oxybutynin in children with urge incontinence due to overactive bladder results of a multicentre observational cohort study
BJUI, 2010Co-Authors: Schahnaz Alloussi, Gerd Murtz, Reinhard Braun, Ulrich Gerhardt, Martina Heinrich, Eva Hellmis, Werner Horn, Daniela Marschallkehrel, Kurt Niklas, Michael RaabeAbstract:Study Type – Therapy (observational cohort) Level of Evidence 2b OBJECTIVE To compare, in a retrospective observational cohort study, the efficacy, tolerability and safety of Propiverine and oxybutynin in children with urge incontinence (UI) due to overactive bladder. PATIENTS AND METHODS Medical records were scrutinized for children with UI. As a primary efficacy outcome variable the achievement of continence after treatment with variable doses of Propiverine or oxybutynin was assessed. Weekly UI episodes and daily voiding frequency were evaluated as secondary efficacy outcomes. Tolerability was evaluated by the rate of adverse events, adverse drug reactions caused by antimuscarinics and premature treatment termination. RESULTS At 16 study centres, 621 children aged 5–14 years with UI due to overactive bladder were enrolled. After anticholinergic treatment (437 Propiverine, 184 oxybutynin) continence was achieved in 61.6% and 58.7% of the patients after 186 and 259 days, respectively. There were clinically relevant improvements in voiding frequency across treatment groups. Daily doses of Propiverine were markedly below the recommendations (0.54 vs 0.8 mg/kg body weight), daily doses of oxybutynin were according to the recommendations (0.31 vs 0.2–0.4 mg/kg body weight) at treatment initiation. There was a significantly more favourable tolerability to Propiverine than oxybutynin for the overall rate of adverse events (3.9% vs 16.3%, odds ratio 4.813), adverse drug reactions caused by Propiverine or oxybutynin (2.8% vs 9.2%) and premature treatment termination due to adverse drug reactions (1.6% vs 4.4%). CONCLUSION Propiverine and oxybutynin are effective in children with UI due to overactive bladder. Sufficient treatment periods of at least 2, preferably 3–4, months are the crucial factors for a successful treatment. The tolerability profile of Propiverine is better than for oxybutynin.
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failure of monotherapy in primary monosymptomatic enuresis a combined desmopressin and Propiverine treatment regimen improves efficacy outcomes
BJUI, 2009Co-Authors: Saladin Helmut Alloussi, Gerd Murtz, Helmut Madersbacher, Gerhard Strugala, Silvia Gitzhofer, Robert Eichel, Christoph Lang, Schahnaz AlloussiAbstract:OBJECTIVE To evaluate, in a prospective study, the combination of the antimuscarinic Propiverine and the antidiuretic hormone-agonist desmopressin in children and adolescents not responsive to previous monotherapy, as in primary monosymptomatic enuresis (PME), combined treatments are considered a second-line approach after the failure of monotherapy. PATIENTS AND METHODS The study included 122 children and adolescents (mean age 10.8 years, range 5–21) with PME and so far unresponsive to single or multiple monotherapy. Propiverine (body weight <30 kg, 15 mg/day; ≥30 kg, 20 mg/day) and desmopressin (0.4 mg/night) were administered over 3 months, followed by successive structured withdrawal programmes for Propiverine and desmopressin, depending on the amount of loss of urine at night before treatment. RESULTS The re-evaluation of unresponsive patients, incorporating video-urodynamics, showed neurogenic detrusor overactivity, isolated detrusor sphincter dyssynergia and vesicorenal reflux in 12.3% (15/122) of patients, so far falsely treated as enuresis. In 107 of 122 patients the diagnosis of PME was confirmed. The primary efficacy outcome, continence at night, was achieved in 104 of 107 patients (97.2%). During the individual follow-up periods (3–12 months), 23 of 107 (21.5%) patients relapsed after withdrawal of both medications. Adverse events of moderate intensity were rare (3.7%). CONCLUSION Re-evaluation of patients after monotherapy has failed is justified, because other entities can be discovered in patients so far treated unsuccessfully for enuresis. The combination of Propiverine and desmopressin is highly effective in children with PME. Our results support the case for further optimizing the inaugurated treatment algorithm of PME for treatment duration, dose-titration and structured withdrawal programmes, thus possibly further decreasing relapse rates.
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Propiverine vs oxybutynin for treating neurogenic detrusor overactivity in children and adolescents results of a multicentre observational cohort study
BJUI, 2009Co-Authors: Helmut Madersbacher, Gerd Murtz, Schahnaz Alloussi, Burghard Domurath, Thomas Henne, Iris Korner, Andreas Niedeggen, Joseph Nounla, Jurgen Pannek, Heinrich SchultebauklohAbstract:OBJECTIVE To compare, in a retrospective observational cohort study, the efficacy, tolerability, safety and clinical effectiveness of Propiverine and oxybutynin in children and adolescents with neurogenic detrusor overactivity (NDO). PATIENTS AND METHODS In all, 255 children and adolescents (aged 1–18 years) with NDO (199 myelomeningocele, 46 spinal cord injury, 10 other diagnoses) were enrolled at 14 study centres. To evaluate the efficacy of Propiverine and oxybutynin, urodynamic and clinical variables were assessed before and after at least 12 month of the antimuscarinic agents administered at variable doses. RESULTS In all, 127 patients given Propiverine and 128 given oxybutynin were enrolled. The primary efficacy outcome, i.e. reductions in urodynamically assessed individual maximum detrusor pressure (Pdetmax), was assumed to indicate success in 74.2% of those on Propiverine vs 49.6% on oxybutynin. The mean Pdetmax was significantly reduced during treatment, from 59.8 to 36.7 cmH2O in the Propiverine and from 65.2 to 54.9 cmH2O in the oxybutynin groups. The mean maximum cystometric bladder capacity increased from 146 to 242 mL in the Propiverine and from 222 to 310 mL in the oxybutynin group. Propiverine was better tolerated than oxybutynin, having fewer adverse drug reactions (9.4% vs 17.2%, odds ratio 2.04), and for its severity grades and premature treatment termination (none vs 11 cases). CONCLUSION In this non-interventional study, reflecting ‘real-life’ clinical practice, comparing the efficacy, tolerability and safety of Propiverine and oxybutynin in children and adolescents with NDO, Propiverine was at least as effective as oxybutynin, but better tolerated, resulting in superior clinical effectiveness than for oxybutynin.
